Submissions for variant NM_000546.6(TP53):c.313G>C (p.Gly105Arg)

dbSNP: rs1060501195

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475325	SCV000545290	pathogenic	Li-Fraumeni syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 105 of the TP53 protein (p.Gly105Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a TP53-related condition (PMID: 15381368; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 406574). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). This variant disrupts the p.Gly105 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 15381368), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492606	SCV000581141	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing	The p.G105R variant (also known as c.313G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 313. The glycine at codon 105 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the functionally critical DNA binding domain and has shown a loss of transactivation activity in yeast based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Although this specific alteration has not been reported in the literature, another alteration at this position (p.G105C) was reported in a family with classic Li-Fraumeni Syndrome, where the proband had three primary breast cancers by the age of 31, and a family history of early onset breast cancer and brain tumors (Bendig I et al., Cancer Genet. Cytogenet. 2004 Oct; 154(1):22-6). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.<br />
Genome-Nilou Lab	RCV000492606	SCV002582411	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289594	SCV002583073	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing